1. Technical Field
The present invention is directed to a vaccine against Neisseria meningitidis Group B, serotype 2. More particularly, the present invention is related to an aluminum hydroxide adjuvanted vaccine containing only a single serotype 2 antigen but being protective against both 2a and 2b meningococcal disease.
2. State of the Art
Although the proportion of Neisseria meningitidis (meningococcal) disease due to the individual serogroups varies from country to country, over 95 percent of the disease is caused by strains of group A, B, C, Y and W135. Highly effective capsular polysaccharide vaccines for serogroups A and C were developed about a decade ago (Gold, et al. Bull WHO 45:279-282, 1969-1970 and Gotschlich, et al. J. Exp. Med. 129:1349-1365. 1969. Recently, the polysaccharides for serogroups Y and W135 have been combined with those of A and C into a tetravalent vaccine (Hankins, et al. Proc. Soc. Biol. Med. 169:54-57. 1982). In contrast, group B capsular polysaccharide vaccines have proven to be essentially nonimmunogenic (Wyle, et al. J. Infect. Dis. 126:514-522. 1972 and Zolllinger, et al. J. Clin. Invest. 63:836-848. 1979) and attempts to improve the polysaccharide's immunogenicity through conjugation to protein have been unsuccessful (Jennings, et al. J. Immunol. 127:104-108. 1981) Serogroup B is presently the major cause of meningococcal disease in most temperate countries, and this combined with the lack of immunogenicity of the B polysaccharide, has necessitated development of alternative vaccines based upon the serotype proteins.
Meningococcal group B and C have been subdivided into 18 different serotypes based upon the immunological specificities of their major outer membrane proteins (Frasch, et al. Infect. Immun. 6:127-133. 1972 and Frasch, et al. J. Exp. Med. 147:629-644. 1978). The currently used procedures for meningococcal serotyping are agar gel double diffusion (Frasch, et al. Infect. Immun. 6:127-133, 1972) inhibition of solid phase radioimmunoassay and coagglutination using monoclonal antibodies adsorbed to protein A Sepharose. For reasons not yet understood only a few of these serotypes are associated with most group B and C disease. Sixty to eighty percent of the disease isolates are serotype 2 (Ashton, et al. Can. J. Microbiol. 26:1480-1488, 1980. and DeMaeyer, et al. J. Infect. 3(Suppl. 1):63-70. 1981) which has caused most B and C meningococcal epidemics (Frasch, et al. Seminars in Infectious Disease, Vol. 2. Stratton Intercontinental Medical Book Corp., NY. 304-337. 1979.)
Serotype 2 has now been subdivided into serotypes 2a, 2b and 2c based upon specific immunodeterminants present on the 41,000 dalton major outer membrane protein (Poolman, et al. J. Gen. Microbiol. 116:465-473. 1980). Serotype 2a was the major serotype associated with disease within group B until around 1980 and is still the major serotype among group C strains (Ashton, et al. Can. J. Microbiol. 29:129-136). Poolman et al, supra has documented the change from 2a to 2b in The Netherlands, and Jones and Eldridge observed that 2b has become more common in England (Abstract: Fifth International Conference on cerebrospinal meningitidis, Marseille, 1983). At present most group B serotype 2 disease is due to serotype 2b (Ashton, 1980, supra).
Serotype 2a protein vaccines have been prepared from outer membranes isolated in the form of membrane vesicles (Frasch, et al. Infect. Immun, 37:271-280. 1982). A number of these vaccines have been examined for toxicity and immunogenicity in animals (Peppler, et al. Infect. Immun. 37:264-270. 1982) and evaluated for safety and immunogenicity in adult volunteers, in whom they were found to be both safe and immunogenic (Frasch, et al). Seminars in Infectious Disease, Vol. 4., 1982; and Zollinger, et al. J. Clin. Invest. 63:836-848, 1979). The solubility characteristics of the protein vaccines were found to be important, because early vaccines which were predominantly protein became insoluble and failed to induce bactericidal antibodies in man (Frasch, et al. Seminars in Infectious Disease, Vol. 4. 1982), although found to be immunogenic in animals (Frasch, et al. J. Exp. Med. 147:629-644, 1978).
Soluble serotype 2a protein vaccines containing noncovalently bound group B meningococcal polysaccharide have been shown to induce serotype 2 specific bactericidal antibodies in several clinical studies (Frasch. Medical Microbiology, Vol. 2. Academic Press, NY. 1983). When these vaccines were evaluated in young children they were found to be less immunogenic than in adults (Frasch, et al. Med. Trop. (Marseille) 43:177-180. 1983), indicating that the use of adjuvants or the like may be required.
While serotype 2 remains the predominant cause of group B Neisseria meningitidis invasive disease in many parts of the world, most of this disease is now believed due to serotype 2b rather than 2a.